Selective Synthesis of Boron-Functionalized Indenes and Benzofulvenes by BCl3-Promoted Cyclizations of ortho-Alkynylstyrenes

A selective, metal-free synthesis of boron-functionalized indenes and benzofulvenes via BCl3-mediated cyclization of o-alkynylstyrenes is described. The method allows precise control over product formation by adjusting reaction conditions. These borylated products were utilized in diverse C–B bond derivatizations and in the total synthesis of Sulindac, a nonsteroidal anti-inflammatory drug, demonstrating the versatility and practicality of the developed methodology for synthetic applications.

C ompounds featuring indene or benzofulvene cores have attracted significant attention due to their applications in materials science, 1 their roles as ligands in metal complexes, 2 and their frequent occurrence in natural products, biologically active molecules and pharmaceuticals (Scheme 1a). 3 A representative example is Sulindac, a nonsteroidal antiinflammatory agent (NSAID) with a benzofulvene skeleton, used for treating pain and inflammation associated with arthritis, gout and other inflammatory diseases.3e,f Numerous synthetic approaches for indenes and benzofulvenes have been described, 4 including electrophilic cyclizations of o-alkynylstyrenes promoted by iodonium sources or catalyzed by gold(I) complexes or B(C 6 F 5 ) 3 /PPh 3 frustrated Lewis pair (Scheme 1b). 5 However, the development of more sustainable, ideally metal-free, strategies for synthesizing easily fuctionalizable derivatives of these privileged scaffolds remains of great importance.
The formation of C−B bonds is crucial in organic chemistry, given the great utility of boron-containing organic compounds in areas such as materials science and medicinal chemistry, 6 as well as synthetic intermediates.Boronic acids and their ester derivatives, known for their stability, ease of storage and handling, high functional group tolerance, and low toxicity, serve as essential and versatile building blocks in several chemical transformations. 7raditionally, the synthesis of organoboronates involves the use of organometallic reagents and/or transition metal complexes. 8These conventional methods often suffer from limitations such as functional group incompatibility, the necessity for harsh reaction conditions or prefunctionalized substrates, and the constraints imposed by the intrinsic selectivity of the starting materials.In the past decade, metalfree C−B bond formation strategies have emerged as more sustainable and practical alternatives, overcoming many of these issues.In this context, borylative heterocyclizations provide a straightforward and regioselective access to heterocycles bearing easily functionalizable boron substituents in their structure.8a,h,9 This innovative methodology simultaneously forms a heterocycle and a C−B bond via an intramolecular cyclization triggered by a nucleophilic attack on a triple bond activated by a boron electrophile.Ingleson developed the analogous carbocyclizations to synthesize Bcontaining dihydronaphtalenes, using alkynyl substrates with an arene acting as an internal nucleophile and simple BCl 3 as activator. 10This method was later applied to deliver B-and B,N-doped polycyclic aromatic hydrocarbons. 11The same group reported the formation of various borylated cycloadducts, including benzofulvenes, in an interesting study on the cyclization of diynes that provides useful mechanistic insights but shows limited synthetic application. 12Recently, the first synthetically useful metal-free borylative enyne cyclization has been reported, using BCl 3 as promoter and o-alkenyl-o′-alkynylbiaryls as substrates, producing borylated phenathrenes through a notable skeletal rearrangement. 13erein, we describe the selective synthesis of boronfunctionalized indenes and benzofulvenes via a metal-free BCl 3 -mediated cyclization of suitable o-alkynylstyrenes (Scheme 1c).Additionally, the utility of the synthesized borylated indenes and the developed metal-free methodology has been demonstrated by a range of C−B bond derivatizations and the total synthesis of Sulindac.
At first, we selected 2′,2′-dimethyl o-(phenylethynyl)styrene 1a as a model substrate and tested its cyclization in the presence of BCl 3 (Scheme 2).Initial experiments using different solvents, temperatures and reaction times led, upon treatment with pinacol and NEt 3 , to mixtures of products among which variable amounts of indene 2a and benzofulvene 4a were observed (see Supporting Information for details).After some optimization, selective cyclization to 2a-BCl 2 was achieved when the reaction was performed at 0 °C using dichloromethane (DCM) as solvent.Remarkably, the conditions subsequently used for the formation of the pinacol ester determined the nature of the product finally obtained.Thus, when it was carried out at 0 °C in short reaction times indene 2a was selectively formed, whereas heating at 60 °C and using prolonged reaction times allowed the exclusive formation of benzofulvene 3a, coming from the elimination of HCl from the initial cyclization product.Compound 2a proved to be unstable during purification by column chromatography with silica gel, leading to 4a.However, 2a could be isolated in good yield by using deactivated silica gel for the purification.Moreover, an increased yield was achieved for the bulkier Bepin derivative. 14The formation of 2a-BCl 2 is proposed to proceed via activation of the alkyne by coordination to BCl 3 followed by nucleophilic attack of the alkene moiety promoting a 5-endo-dig cyclization.The carbocationic intermediate would then be trapped by a chloride anion.Some experiments were performed to unveil the origin of this chloride.Thus, compound 2a was also obtained using chlorobenzene as the solvent, which is more robust to halide loss than DCM.In addition, indene 5a, incorporating a bromine atom, was exclusively formed using BBr 3 instead of BCl 3 .Therefore, both experiments suggest that the halogen atom present in the final product comes from the boron source.
Once optimal conditions for the selective synthesis of the desired cycloadducts 2a or 3a had been established, we explored the scope of both transformations.The reaction of oalkynylstyrenes 1 with BCl 3 at 0 °C in CH 2 Cl 2 followed by treatment with pinacol and NEt 3 at 0 °C allowed the synthesis of diverse borylated indenes 2 with substituents of different electronic and steric nature (Scheme 3).Regarding the substitution at the alkyne of the starting enynes 1, aryl groups with both electron-donating (2b,c) and electron-withdrawing substituents, in either para-, meta-, or ortho positions (2d−f), were well tolerated.In addition, a polycyclic aryl (2g) as well as a heteroaromatic ring (2h) in this position provided excellent results.Moreover, an alkenyl group can also be incorporated (2i), although in moderate yield due to a partial HCl elimination in the reaction medium, leading to 4i.Conversely, alkyl groups are also compatible with the developed method and result in the formation of the corresponding indenes 2j−l in good yields. 15Finally, borylated indenes bearing substituents in different positions of the benzene ring (2m−o) can also be efficiently synthesized following this methodology.Notably, the reaction can be scaled up to 1 mmol while maintaining high yields.However, a limitation of this method is that o-alkynylstyrenes with aryl groups as substituents of the alkene moiety do not produce indenes 2. Instead, elimination occurs to form benzofulvenes 3p,q, which is favored due to conjugation and can not be avoided.
On the other hand, performing the treatment with pinacol and triethylamine at 60 °C for 14 h, after the completion of the borylative cyclization, allowed the synthesis of various borylated benzofulvenes 3 (Scheme 4).Arenes bearing electron-donating (3b,c) or -withdrawing groups in either para-or meta-positions (3d,e) are suitable substituents at the alkyne of the starting enynes 1.However, the elimination was Scheme 1. Background and Proposal Scheme 2. Initial Experiments Organic Letters hampered when a more sterically hindered ortho-substituted ring was present, resulting in a mixture of 2f and 3f in the crude reaction, with low conversion toward 3f (15%).A similar result was observed when using naphthyl-substituted enyne 1g (30% conversion toward 3g).In addition, thiophenylsubstituted benzofulvene 3h was prepared in lower yield due to its partial decomposition under the reaction conditions.On the contrary, both alkenyl and alkyl groups are well tolerated in this transformation, yielding the corresponding borylated benzofulvenes 3i−l efficiently.Moreover, reactions involving substrates substituted at the internal arene produced the corresponding benzofulvenes 3m,o in high yields.Notably, diverse substitutions can be introduced in the exocyclic alkene of the carbocycle.Thus, benzofulvenes 3p,q mono-and diaryl substituted on the external alkene could be synthesized in high yields, and a cyclic substituent at that position also proved compatible with this methodology (3r).
The synthetic usefulness of borylated benzofulvenes 3 as building blocks was preliminarily demonstrated with different transformations of 3a, selected as a model (Scheme 5).It can be easily converted into the corresponding potassium trifluoroborate salt (6a) or protodeborylated to yield benzofulvene 8a.Additionally, it participates in Suzuki couplings for the introduction of aromatic substituents at position 3 (7a) and can be efficiently oxidized to ketone 9a.
Finally, to further demonstrate the utility of the developed methodology, it has been applied to the synthesis of Sulindac.To this end, o-alkynylstyrene 1s was prepared from commercially available reagents and cyclized in the presence of BCl 3 (Scheme 6).For this particular substrate, it was necessary to heat at 70 °C and employ 4 equiv of the boron electrophile to promote the reaction and to add TBP to avoid partial deborylation of the final product in the reaction medium.Under these conditions, borylated benzofulvene 3s was obtained in high yield as a mixture of Z/E isomers.Next, a  Organic Letters palladium catalyzed coupling between 3s and α-bromoethyl acetate provided 10s, also as a Z/E mixture.Treatment of 10s with HCl in acetic acid not only performed the anticipated hydrolysis of the ester group, but also promoted the convergence of both alkene isomers into the desired Z olefin.Finally, Sulindac was obtained by oxidation of the sulfide to the corresponding sulfoxide.
In summary, we have presented a mild and versatile metalfree approach for the synthesis of borylated indenes and benzofulvenes using easily accessible o-alkynylstyrenes.These reactions occur in high yield, with wide scope and complete selectivity, controllable by simple adjustment of reaction temperature in the derivatization of the initially formed BCl 2 -indenes into isolable pinacol boronate esters.The utility of the resulting borylated building blocks is evidenced by their diverse functionalization at the C−B bond.Moreover, the developed methodology serves as a key step in the synthesis of Sulindac, a nonsteroidal anti-inflammatory drug.Overall, this work extends the applicability of metal-free borylative cyclizations, providing access to valuable B-indenes and benzofulvenes from readily available starting materials, complementing the existing metal-based strategies.